Malignant tumors represented by carcinoma are diseases caused by abnormal growth of cells, and the most distinctive characteristic of malignant tumors is invasion into the surrounding tissue and metastasis to other organs. It has been long known that the leading cause of death for malignant tumor patients is not the growth of the primary lesion but multiple organ failure resulting from distant metastasis of the tumor cells. However, control of malignant tumor metastasis has not yet been achieved so far and is one of the most crucial issues in the whole area of cancer treatment.
Metastasis of an epithelial malignant tumor (carcinoma) is considered to be caused by various physiological phenomena of cancer cells, such as the acquisition of motility and migrating ability typified by epithelial to mesenchymal transition (hereinafter, abbreviated to “EMT”), invasion into the surrounding tissue, migration and invasion into blood vessels and lymphatic vessels, colonization in vascular endothelium of distant tissue, metastatic lesion formation, etc.
Also in a non-epithelial malignant tumor (sarcoma etc.), tumor cells that have become malignant and acquired motility and migrating ability invade blood vessels etc., colonize vascular endothelium of distant tissue, invade the tissue, and then form a metastatic lesion.
In this process, interaction between endothelial selectins of blood vessels, in particular capillary vessels, and selectin ligands expressed on tumor cells is involved in the colonization of circulating tumor cells in vascular endothelium (Non Patent Literature 1). It is also known that inflammatory cytokines (IL-1β, TNF-α) promote the adhesion of tumor cells to vascular endothelium cells (Non Patent Literature 2 and 3). For example, inflammatory cytokines caused by surgery or a surgery-induced infection systemically and locally promote the adhesion of tumor cells to vascular endothelium cells and facilitate the metastasis of the tumor cells to distant tissue and tumor recurrence at the primary site (Non Patent Literature 1 to 3).
In the prevailing pharmacological treatment for cancer, an anticancer agent and/or an antitumor agent is administered to a tumor-bearing patient usually for the purpose of reducing the size of the primary focus, and the effect of the anticancer agent and/or the antitumor agent is judged by the reduction percentage. However, an anticancer/antitumor agent is often harmful to normal tissue, and so-called “adverse effects” that cause various organ disorders appear at a high rate. Therefore, chronic dosing of an anticancer agent and/or an antitumor agent causes problems of such serious side effects. For this reason, in actual cancer treatment, the administration of an anticancer agent and/or an antitumor agent has often to be restricted in terms of the amount and duration, leading to shortened life expectancy.
Meanwhile, in the living body, angiotensinogen is converted, via renin, into angiotensin I, which is further converted by converting enzymes, such as angiotensin converting enzyme (ACE), into angiotensin II (AngII), which has various strong physiological functions.
As a receptor to which the aforementioned AngII binds, angiotensin receptors type 1 (hereinafter referred to as AT1 receptors) and AT2 receptors have been identified. The hitherto known effects of AngII, such as pressor effect, vasoconstriction effect, etc. have been understood to be mainly mediated by classical AT1 receptors. Meanwhile, the functions of AT2 receptors have been rapidly revealed in recent years. AT2 receptors antagonize AT1 receptors in many cells and tissues, and act in the direction of inhibiting the onset and progress of diseases, in particular, in the direction of pressure lowering, cell growth inhibition, hypertrophy inhibition, apoptosis promotion, and extracellular matrix production inhibition. AT2 receptors are widely and highly expressed in a fetal period, but the expression level rapidly decreases after birth. However, it has become known that, under certain diseases, such as vascular disorders, and cardiovascular remodeling after myocardial infarction, re-expression of AT2 receptors occurs in a tissue-specific manner, and the importance of AT2 receptors in the inhibition of the onset and progress of various diseases attracts attention.
General pharmacological effects that can be predicted to be exerted as a result of activating AT2 receptors are also reported in a paper by de Gasparo and others (Non Patent Literature 4), and AT2 receptor agonists are expected to exert therapeutic or preventive effects on various diseases in the medical use. Target diseases include many groups of diseases in which the renin-angiotensin-aldosterone system (hereafter referred to as RAAS) is involved, for example, metabolic diseases and circulatory diseases. Specific examples thereof include cerebral infarction, renal disease, heart disease, hypertension, diabetes mellitus, metabolic syndrome, etc.
As a non-peptidic AT2 receptor agonist, so far disclosed are 3-phenyl-2-thiophenesulfonamide and a biphenyl sulfonamide compound (Non Patent Literature 5 and 6, Patent Literature 1 to 9).
Also, it is described that CGP44112A, which is a peptidic AT2 receptor agonist, inhibits the growth of cancer cells and promotes apoptosis, and thereby inhibits the metastasis of colorectal cancer to the liver (Non Patent Literature 7).
Meanwhile, sulfonyl malonamide derivatives are known as an AT2 receptor agonist, but it is not disclosed that the derivatives suppress cancer metastasis (Patent Literature 10). In addition, sulfonyl malonamide derivatives are known as an herbicide (Patent Literature 11).
However, it has been unknown that non-peptidic AT2 receptor ligands, in particular, non-peptidic AT2 receptor agonists, suppress the metastasis of a malignant tumor (it has especially been unknown that they suppress the metastasis of a malignant tumor without targeting the malignant tumor itself).
Patent Literature 12 discloses medicines for suppressing or preventing the metastasis of a malignant tumor, the medicines comprising, as an active ingredient, vascular endothelial intracellular cGMP enhancers, such as a natriuretic peptide receptor GC-A agonist, but does not disclose the effects of a non-peptidic AT2 receptor ligand, in particular, a non-peptidic AT2 receptor agonist, on the metastasis of a malignant tumor.